The process of forming new blood vessels is termed angiogenesis. During angiogenesis, vascular endothelial cells undergo orderly proliferation, migration, and morphogenesis to form new capillary networks. Under normal or non-pathologic conditions, angiogenesis occurs under well-defined conditions such as in wound healing, in response to ischemia, and during embryonal and fetal development. However, persistent or uncontrolled angiogenesis can lead to a variety of disease states or conditions and, in the case of solid tumors, may be a necessary condition to maintain the disease state.
Many extracellular and intracellular signaling molecules interact with cellular receptors and regulate effects in the vascular system, including processes related to angiogenesis. Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid that mediates a wide variety of cellular responses through interaction with the members of the endothelial cell differentiation gene family (EDG also known as S1Pn receptors) of plasma membrane-localized G protein-coupled receptors. To date, five members of this family have been identified as S1P receptors in different cell types, S1P1/EDG-1, S1P2/EDG-5, S1P3/EDG-3, S1P4/EDG-6 and S1P5/EDG-8. In particular, S1P interaction with the S1P1 and S1P3 receptors has been demonstrated to play an important role in survival and morphogenesis of endothelial cells in vitro and S1P1 is necessary for vascular maturation in vivo. However, S1P also exerts potent effects on other organ systems, such as the immune system and the reproductive system, indicating that it is a multifunctional lipid mediator.
S1P and its receptors are involved in the regulation of vasculature. It is thus desirable to manipulate S1P receptors, particularly in the treatment of diseases of the vascular system.